RESUMEN
Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Cerebelosas/tratamiento farmacológico , Meduloblastoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adolescente , Biomarcadores de Tumor/metabolismo , Niño , Ciclofosfamida/uso terapéutico , Femenino , Humanos , Ifosfamida/uso terapéutico , Masculino , Meduloblastoma/metabolismo , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Supervivencia sin ProgresiónRESUMEN
In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes1-3. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5' splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5' cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer.
Asunto(s)
Neoplasias Cerebelosas/genética , Proteínas Hedgehog/genética , Meduloblastoma/genética , ARN Nuclear Pequeño/genética , Adolescente , Adulto , Empalme Alternativo , Proteínas Hedgehog/metabolismo , Humanos , Mutación , Sitios de Empalme de ARN , Empalme del ARNRESUMEN
We describe an unusual leukoencephalopathy in a female who developed global language and memory difficulties as well as diffuse FLAIR lesions in the cerebral white matter (WM) ~ 30 months after bariatric surgery. She had no detectable nutritional deficiency. She died suddenly due to cardiovascular disease. The cerebral WM revealed perivascular T-cell infiltrations and strong immunoreactivity for the amyloid precursor protein limited to axons, without signs of myelin or neuronal injury. Unexplained WM lesions have been reported in post-bariatric-surgery patients. Our findings suggest that altered immunity and axonal dysfunction could be responsible for leukoencephalopathy in some patients undergoing bariatric procedures.â©.
Asunto(s)
Derivación Gástrica/efectos adversos , Leucoencefalopatías/diagnóstico por imagen , Complicaciones Posoperatorias/diagnóstico por imagen , Encéfalo/patología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/cirugía , Electroencefalografía , Femenino , Humanos , Hipertensión/complicaciones , Inflamación/diagnóstico por imagen , Inflamación/etiología , Leucoencefalopatías/etiología , Imagen por Resonancia Magnética , Persona de Mediana Edad , Pruebas Neuropsicológicas , Obesidad/complicaciones , Obesidad/cirugía , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: The term "tumor-to-lesion metastasis" is an extension of "tumor-to-tumor metastasis," which is a rare but well-documented phenomenon. Tumor metastasis to the meninges and/or central nervous system (CNS) is rare in patents with multiple sclerosis (MS), although MS lesions bear many similarities to the primary tumor microenvironment and metastatic niche. We present the first case of malignant tumor metastasis to MS lesions with immunophenotyping of inflammatory cells in the metastatic foci. CASE DESCRIPTION: A 45-year-old male patient with a 6-year history of MS and newly diagnosed lung carcinoma developed carcinoma metastases in the meninges and CNS, as well as into mixed active/inactive MS lesions. The carcinoma-hosting MS lesions exhibited abundant macrophages/microglia with ongoing demyelination but rare T cells. In comparison, a 46-year-old female patient with a 21-month history of MS and newly diagnosed gastric carcinoma was found to have leptomeningeal carcinomatosis and separate active MS lesions containing not only frequent macrophages/microglia but also T cells. CONCLUSIONS: The carcinoma-hosting MS lesions are unlike typical active lesions but recapitulate the CNS metastatic niche. Our observations suggest that metastasis-hosting MS lesions might require a distinct immune microenvironment to be permissive to the seeding and growth of metastatic tumors.
Asunto(s)
Neoplasias Pulmonares/patología , Meninges/cirugía , Esclerosis Múltiple/patología , Neoplasias Gástricas/patología , Femenino , Humanos , Macrófagos/patología , Masculino , Meninges/patología , Microglía/patología , Esclerosis Múltiple/diagnóstico , Metástasis de la NeoplasiaRESUMEN
Recurrent mutations in chromatin modifiers are specifically prevalent in adolescent or adult patients with Sonic hedgehog-associated medulloblastoma (SHH MB). Here, we report that mutations in the acetyltransferase CREBBP have opposing effects during the development of the cerebellum, the primary site of origin of SHH MB. Our data reveal that loss of Crebbp in cerebellar granule neuron progenitors (GNPs) during embryonic development of mice compromises GNP development, in part by downregulation of brain-derived neurotrophic factor (Bdnf). Interestingly, concomitant cerebellar hypoplasia was also observed in patients with Rubinstein-Taybi syndrome, a congenital disorder caused by germline mutations of CREBBP. By contrast, loss of Crebbp in GNPs during postnatal development synergizes with oncogenic activation of SHH signaling to drive MB growth, thereby explaining the enrichment of somatic CREBBP mutations in SHH MB of adult patients. Together, our data provide insights into time-sensitive consequences of CREBBP mutations and corresponding associations with human diseases.
Asunto(s)
Acetiltransferasas/metabolismo , Proteína de Unión a CREB/metabolismo , Proteína de Unión a CREB/fisiología , Proteínas Hedgehog/metabolismo , Meduloblastoma/patología , Mutación , Síndrome de Rubinstein-Taybi/patología , Adulto , Animales , Proteína de Unión a CREB/genética , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/metabolismo , Neoplasias Cerebelosas/patología , Femenino , Proteínas Hedgehog/genética , Humanos , Meduloblastoma/genética , Meduloblastoma/metabolismo , Ratones , Ratones Noqueados , Neuronas , Fenotipo , Síndrome de Rubinstein-Taybi/genética , Síndrome de Rubinstein-Taybi/metabolismo , Transducción de SeñalAsunto(s)
Neoplasias Encefálicas/diagnóstico , Glándula Pineal/patología , Pinealoma/diagnóstico , Tumores Fibrosos Solitarios/diagnóstico , Anciano , Neoplasias Encefálicas/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Glándula Pineal/diagnóstico por imagen , Pinealoma/complicacionesRESUMEN
We describe a 50-year-old man with a well-demarcated intra- and extrasellar lesion and clinical signs of a non-functioning pituitary adenoma. Neuropathological examination revealed tumor composed of non-pigmented spindle cells arranged in tightly packed nests separated by delicate vascular septae. There was no significant cellular atypia or mitotic activity, and Ki67-positive nuclei were present in less than 1% of cells. The neoplastic cells were positive for S-100 and vimentin, and negative for numerous cellular markers including HMB45, anti-melanoma cocktail antibodies, and Masson melanin stain. Electron microscopy revealed scattered cells with small numbers of premelanosomes, aiding in the correct diagnosis of an amelanotic melanocytoma. This is the first case report of entirely amelanotic melanocytoma of meninges, and in a very unique location. BRAF was negative supporting the diagnosis of intracranial origin of the tumor. Approximately 2 years after subtotal resection and stereotactic radiosurgery the patient is alive and well with a non-progressive residual tumor.â©.
Asunto(s)
Adenoma/patología , Diagnóstico Diferencial , Melanoma Amelanótico/patología , Neoplasias Meníngeas/patología , Neoplasias Hipofisarias/patología , Adenoma/diagnóstico , Humanos , Masculino , Melanoma Amelanótico/diagnóstico , Neoplasias Meníngeas/diagnóstico , Persona de Mediana Edad , Neoplasias Hipofisarias/diagnósticoRESUMEN
While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.
Asunto(s)
Meduloblastoma/clasificación , Medicina de Precisión , Análisis por Conglomerados , Estudios de Cohortes , Variaciones en el Número de Copia de ADN , Metilación de ADN , Perfilación de la Expresión Génica , Genómica , Humanos , Meduloblastoma/genética , Meduloblastoma/terapiaRESUMEN
We describe an atypical teratoid rhabdoid tumor (AT/RT) with a component of low-grade and anaplastic rhabdoid meningioma in a 7-year-old child. The AT/RT was uniformly negative for INI1 and displayed immunoreactivity for vimentin, P53, CD99, cytokeratins with AE1/AE3 antibodies, epithelial membrane antigen, ß-catenin, smooth muscle actin, E-cadherin, and S-100 protein. AT/RT was continuous, with small foci of recognizable low-grade and anaplastic meningioma. The low-grade meningioma was INI1 positive with scattered INI1-negative nuclei, whereas the remaining tumor components were INI1 negative. A recurrent tumor 6 months after partial resection contained only INI1-negative AT/RT. This case supports the hypothesis that rare examples of AT/RT may emerge from a preexisting "parent" neoplasm as a result of a second hit mutation.
Asunto(s)
Neoplasias Meníngeas/patología , Meningioma/patología , Neoplasias Primarias Múltiples/patología , Tumor Rabdoide/patología , Teratoma/patología , Niño , Humanos , MasculinoAsunto(s)
Neuroma Acústico/diagnóstico , Neuroma Acústico/patología , Anciano , Carcinoma de Células Escamosas/complicaciones , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patología , Transformación Celular Neoplásica , Quiste Epidérmico/complicaciones , Quiste Epidérmico/diagnóstico , Quiste Epidérmico/patología , Femenino , Humanos , Neuroma Acústico/complicacionesRESUMEN
We report a childhood case of thalamic atypical extraventricular neurocytoma that progressed to highly anaplastic ganglioglioma after 8 years of dormancy after subtotal resection and chemotherapy. The neurocytoma displayed immunoreactivity only for synaptophysin, ß-catenin, S100, and CD56. The ganglioglioma acquired strong immunoreactivity for chromogranin, glial fibrillary acidic protein, neuron-specific enolase, and p53 and showed a very high proliferation rate approaching 50% in some areas. Tumor transformation was associated with overexpression of components of the sonic hedgehog and Wnt developmental signaling pathways, which are known to regulate tumor-initiating cells in malignant brain neoplasms.
Asunto(s)
Neoplasias del Tronco Encefálico/patología , Transformación Celular Neoplásica/patología , Ganglioglioma/patología , Neurocitoma/patología , Tálamo/patología , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Biopsia , Neoplasias del Tronco Encefálico/química , Neoplasias del Tronco Encefálico/genética , Neoplasias del Tronco Encefálico/terapia , Proliferación Celular , Transformación Celular Neoplásica/química , Transformación Celular Neoplásica/genética , Niño , Progresión de la Enfermedad , Resultado Fatal , Femenino , Ganglioglioma/química , Ganglioglioma/genética , Humanos , Inmunohistoquímica , Lactante , Imagen por Resonancia Magnética , Neoplasia Residual , Neurocitoma/química , Neurocitoma/genética , Neurocitoma/terapia , Tálamo/química , Factores de TiempoAsunto(s)
Hematoma Subdural Agudo/fisiopatología , Leucemia Mieloide/complicaciones , Placa Aterosclerótica/etiología , Sarcoma/complicaciones , Adulto , Antígenos CD/metabolismo , Escala de Coma de Glasgow , Humanos , Leucemia Mieloide/diagnóstico por imagen , Masculino , Neuroimagen , Sarcoma/diagnóstico por imagenRESUMEN
PURPOSE: Clonal evolution of cancer may be regulated by determinants of stemness, specifically self-renewal, and current therapies have not considered how genetic perturbations or properties of stemness affect such functional processes. Glioblastoma-initiating cells (GICs), identified by expression of the cell surface marker CD133, are shown to be chemoradioresistant. In the current study, we sought to elucidate the functional role of CD133 in self-renewal and identify compounds that can specifically target this CD133(+) treatment-refractory population. EXPERIMENTAL DESIGN: Using gain/loss-of-function studies for CD133 we assessed the in vitro self-renewal and in vivo tumor formation capabilities of patient-derived glioblastoma cells. We generated a CD133 signature combined with an in silico screen to find compounds that target GICs. Self-renewal and proliferation assays on CD133-sorted samples were performed to identify the preferential action of hit compounds. In vivo efficacy of the lead compound pyrvinium was assessed in intracranial GIC xenografts and survival studies. Lastly, microarray analysis was performed on pyrvinium-treated GICs to discover core signaling events involved. RESULTS: We discovered pyrvinium, a small-molecule inhibitor of GIC self-renewal in vitro and in vivo, in part through inhibition of Wnt/ß-catenin signaling and other essential stem cell regulatory pathways. We provide a therapeutically tractable strategy to target self-renewing, chemoradioresistant, and functionally important CD133(+) stem cells that drive glioblastoma relapse and mortality. CONCLUSIONS: Our study provides an integrated approach for the eradication of clonal populations responsible for cancer progression, and may apply to other aggressive and heterogeneous cancers.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Glicoproteínas/antagonistas & inhibidores , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Péptidos/antagonistas & inhibidores , Compuestos de Pirvinio/farmacología , Antígeno AC133 , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Proliferación Celular , Autorrenovación de las Células/efectos de los fármacos , Autorrenovación de las Células/genética , Modelos Animales de Enfermedad , Expresión Génica , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Redes Reguladoras de Genes , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/mortalidad , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Péptidos/genética , Péptidos/metabolismo , Pronóstico , Transducción de Señal/efectos de los fármacos , Esferoides Celulares , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: Myxopapillary ependymoma (MPE) is a distinct histologic variant of ependymoma arising commonly in the spinal cord. Despite an overall favorable prognosis, distant metastases, subarachnoid dissemination, and late recurrences have been reported. Currently, the only effective treatment for MPE is gross-total resection. We characterized the genomic and transcriptional landscape of spinal ependymomas in an effort to delineate the genetic basis of this disease and identify new leads for therapy. EXPERIMENTAL DESIGN: Gene expression profiling was performed on 35 spinal ependymomas, and copy number profiling was done on an overlapping cohort of 46 spinal ependymomas. Functional validation experiments were performed on tumor lysates consisting of assays measuring pyruvate kinase M activity (PKM), hexokinase activity (HK), and lactate production. RESULTS: At a gene expression level, we demonstrate that spinal grade II and MPE are molecularly and biologically distinct. These are supported by specific copy number alterations occurring in each histologic variant. Pathway analysis revealed that MPE are characterized by increased cellular metabolism, associated with upregulation of HIF1α. These findings were validated by Western blot analysis demonstrating increased protein expression of HIF1α, HK2, PDK1, and phosphorylation of PDHE1A. Functional assays were performed on MPE lysates, which demonstrated decreased PKM activity, increased HK activity, and elevated lactate production. CONCLUSIONS: Our findings suggest that MPE may be driven by a Warburg metabolic phenotype. The key enzymes promoting the Warburg phenotype: HK2, PKM2, and PDK are targetable by small-molecule inhibitors/activators, and should be considered for evaluation in future clinical trials for MPE.
Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Ependimoma/genética , Neoplasias de la Columna Vertebral/genética , Transcriptoma/genética , Adulto , Anciano , Ependimoma/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Hexoquinasa/biosíntesis , Hexoquinasa/genética , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/biosíntesis , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Proteínas Serina-Treonina Quinasas/biosíntesis , Proteínas Serina-Treonina Quinasas/genética , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora , Médula Espinal/patología , Neoplasias de la Columna Vertebral/patologíaRESUMEN
Hemangiomas are customarily described as low-grade vascular tumors most often located in the head and neck, but on rare occasions occurring in the intradural space of the spine. The different subtypes of hemangiomas can be distinguished histologically as capillary, cavernous, or mixed types. We describe a rare case of a mixed capillary-cavernous extramedullary intradural hemangioma of the thoracic spinal cord, mimicking meningioma radiologically.
Asunto(s)
Capilares/cirugía , Diagnóstico Diferencial , Hemangioma Cavernoso/cirugía , Neoplasias Meníngeas/diagnóstico , Meningioma/diagnóstico , Neoplasias de la Médula Espinal/cirugía , Neoplasias de la Columna Vertebral/cirugía , Capilares/patología , Femenino , Hemangioma Cavernoso/diagnóstico , Hemangioma Cavernoso/patología , Humanos , Persona de Mediana Edad , Neoplasias de la Médula Espinal/diagnóstico , Neoplasias de la Médula Espinal/patología , Neoplasias de la Columna Vertebral/diagnóstico , Neoplasias de la Columna Vertebral/patologíaRESUMEN
TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6%±8.7%, respectively (p<0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89%±2% vs. 57.4%±1.8% (p<0.01)). In contrast, ß-catenin mutation sensitized TP53 mutant cells to radiation (p<0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5%±1.5% in lithium treated cells vs. 56.6±3% (p<0.01)) accompanied by increased number of γH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33%±8% for lithium treated cells vs. 27%±3% for untreated controls (p=0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.
Asunto(s)
Neoplasias Cerebelosas/genética , Litio/farmacología , Meduloblastoma/genética , Mutación/genética , Proteína p53 Supresora de Tumor/genética , Proteínas Wnt/metabolismo , Vía de Señalización Wnt/efectos de los fármacos , Adolescente , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Supervivencia Celular/efectos de la radiación , Neoplasias Cerebelosas/mortalidad , Neoplasias Cerebelosas/patología , Neoplasias Cerebelosas/radioterapia , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Cooperación Internacional , Masculino , Meduloblastoma/mortalidad , Meduloblastoma/patología , Meduloblastoma/radioterapia , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/efectos de la radiación , Radioterapia/efectos adversos , Proteína p53 Supresora de Tumor/metabolismo , Adulto Joven , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
BACKGROUND: Statins have recently been reported to cause a rare autoimmune inflammatory and/or necrotic myopathy that begins or persists after drug cessation. METHODS: We report on 26 patients seen at a neuromuscular centre between 2005 and 2011 who demonstrated muscle weakness/myalgias and creatine kinase elevations during or after statin treatment with continuation of signs and symptoms despite statin withdrawal. RESULTS: All patients were treated with immunosuppressive therapy with good response; all improved biochemically and 86% improved clinically. Sixty-five percent of patients who attempted to taper off immunosuppressive therapy relapsed. We report on a novel finding whereby five of the seven patients who underwent multiple biopsies throughout their disease demonstrated a transformation of their histological diagnosis, with four progressing from having myofibre necrosis with minimal or no inflammation to a diagnosis of polymyositis. CONCLUSIONS: This study offers preliminary evidence that statin-associated necrotizing myopathy and statin-associated polymyositis may not be separate entities but are part of the same pathophysiological spectrum. Both entities respond well to immunosuppression.
Asunto(s)
Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/fisiopatología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Enfermedades Musculares/inducido químicamente , Enfermedades Musculares/fisiopatología , Anciano , Anciano de 80 o más Años , Enfermedades Autoinmunes/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Musculares/diagnóstico , Estudios RetrospectivosRESUMEN
Merkel cell carcinoma is an aggressive neuroendocrine tumor occasionally demonstrating aberrant differentiation to other epithelial and nonepithelial cell lines. We describe a case of Merkel cell carcinoma displaying unique patterns of differentiation in the primary focus and brain metastasis. The skin primary was almost uniformly small cell carcinoma positive for epithelial and neuroendocrine markers, with a few glial fibrillary acidic protein- and cytokeratin 20-positive cells. The neoplasm contained giant cells immunoreactive for neurofilament and negative for epithelial markers. The neck lymph node metastasis was a typical neuroendocrine Merkel cell carcinoma positive for cytokeratin 20. A solitary dural intracranial metastasis displayed features of aggressive ganglioneuroblastoma, expressing many neuronal antigens with no evidence of glial or epithelial differentiation. After total gross resection, the tumor recurred within 3 months, and the patient developed skeletal metastases and died 6 months after craniotomy.